1, 1&#39;-alkylenedipiperazines and methods of preparing same



United States Patent 1,1'-ALKYLENEDIPIPERAZINES AND METHODS OF PREPARINGSANIE Frederick L. Bach, Jr., and Herbert J. Brahauder, Pearl River, andSamuel Kushner, Nanuet, N. Y., assignors to American Cyanamid Company,New York, N. Y., a corporation of Maine No Drawing. Application July 23,1954, Serial No. 445,452

4 Claims. (Cl. 260-268) This invention relates to a new series oforganic compounds. More particularly, this invention relates to certain1,l'-alkylenedipiperazines, their quaternary and mineral acid salts, andmethods for their preparation.

Considerable difliculty has been encountered in the past in thesynthesis of orally active, non-toxic, adrenergic blocking agents. Thisis particularly true where such compounds are intended for use in thetreatment of hypertensive states. In such cases the prescribed course oftherapy usually requires administration of the drug over a prolongedperiod of time. If the drug is toxic, such prolonged administration mayresult in the manifestation of undesirable side effects such asheadache, nasal congestion, drowsiness, nausea, myosis, diarrhea andtachycardia.

We 'have now discovered a series of synthetic organic compounds whichare extremely effective as hypotensive agents and vasodilators. Thecompounds of the present invention have an effective dose in the rangeof 0.5 milligram per kilogram of body weight, are relatively nontoxicand maybe administered orally. The latter property is most advantageousinasmuch as many of the avail able hypotensiveagents must beadministered intravenously in order to produce a maximal physiologicalresponse.

Another desirable property of the compounds of the present inventionresides in their ability toinduce long term blood pressure depressionwith one eifective dose. Thus, following administration of one averagedose, blood pressure may remain reduced for a period longer than 5 hourswithout the necessity for repeated administration.

The compounds of the present invention are those having the followinggeneral formula:

wherein n is a positive integer from 2 to 10, R1 is a phenyl radical andR2 is a heterocyclic radical. As examples of heterocyclic substituentsmay be given pyrimi-dyl, pyridyl, and pyrazinyl. The quaternary andmineral acid salts of these compounds are intended to be included withinthe scope of the present invention.

It is preferred that an inert organic solvent also be present in thereaction mixture. Among the solvents which may be used are the loweralkyl alcohols such as methanol, ethanol and propanol; benzene, toluene,chlorobenzene, dioxane, chloroform and aqeous-alcoholic mixtures. Inaddition, organic bases such as pyridine, quinoline and the like may beused. These latter comaction is one in which an organic solvent isemployed, it-

is possible to carry out the condensation in the absence of suchsolvent. An excessquantity of the piperazine startin-gmaterial is usedin such cases. The piperazine being basic in character, acts as the acidacceptor in lieu of the organic solvent.

Any alkali metal carbonate, bicarbonate or hydroxide may be used as thebase in lieu of the sodium bicarbonate in the above reaction, as forexample potassium or sodium hydroxide, potassium or sodium carbonate andthe like. In addition, the alkali metal amides may be used, as forexample sod-amide or potassium amide.

It is preferred to carry out thereaction at reflux temperatures in orderto minimize the time required for the reaction to reach completion.Although lower temperatures such as room temperature are suitable, alonger period of time may be required when this. is done. A period ofabout 1-30 hours is sufiicient when the reaction is carried out atreflux temperature, whereas a week or more may be required at roomtemperature. If the reaction is carried out at reflux in the absence ofa solvent, the solids are fused before being subjected to refluxing.

The quaternary or mineral acid salts of the compounds of the presentinvention may be readily prepared by known methods. may be treated withmethyl iodide in the presence of an inert organic solvent in which the,base is soluble, as for example benzene, ether, chloroform, and thelike. Upon standing at room temperature for a period of about 1 hour to3 days, depending upon the nature of the base used, the quaternary saltis deposited from solution. In a similar manner, treatment of thedi-piperazine base with a hydrohalogen gas such as hydrogen chloride orhydrogen bromide, or a mineral acid such as sulfuric or phosphoric acid,results in the formation of the corresponding salt. It is preferred tocarry out the reaction in the presence of an inert nonrhydroxylicorganic solvent such as benzene, chloroform or toluene.

In order to obtain maximum yields, a slight modification of the aboveprocedure vis necessary for the purpose of minimizing the formation ofspiro compounds. These compounds areusually formed in cases where n inthe above general formula is equal to 4 or 5. Accordingly, when it isintended to, prepare a compound of this type, the ,haloalkane is addeddrop-wise to a refluxing mixture of the pipera'zine starting material inthe presence of the base. Since the amine is present initially in largeexcess, the formation of a spiro piperazinium compound is minimized. Inthe event any spiro compound is formed however, it may be readilyremoved by washing the may be readily effected when it is desired toprepare unsymmetrical compouuds, as for example when it is desired toprepare a compound wherein R1 in the above general formula is a phenylradical, and R2 is a pyridyl radical. In such cases it is preferablefirst to prepare a 1-omega-haloalkyl-4-substituted piperazine and thenre-' act that compound with a l-substituted piperaz-ine. The

For example, the di-piperazine base .9 last step of the reaction may bemore readily exemplified pheny1)piperazinyl] 2 [[1 [4 (2 4 pyrimidyl)jpiperby the following equation: azinyl] lethane, prepared by reacting1-( fl-chloroethyD- OH OH on H -N\ /N-CH2-CH2C1 HN\ /N- CHI-0H2 OKs-CH2N CHz-CH: GHQ-0H2 N\ /NUH2CHr-N\ /N- out-0H2 oer-0H1 N In moreparticular detail it may be stated that the 4-phenylpiperazine with1-(2-pyrimidyl)piperazine; 1-[1- l-omega-haloalkyl-4-sub-stitutedpiper-azine shown above (4-phenyl)piperazinyll 3 [[1 [4 (2 pyrazinyl)]-may first be prepared by reacting a 1-substitutedpiperpiperazinylllpropane prepared by reacting l-('y-chlor0- azine witha polymethylene halohydrin such as ethylenepropyl) 4 phenylpiperazinewith 1 (2 pyrazinyl)- bromhydrin or propylenechlorhydrin in the presenceof a piperazine; 1-{l-(4-phenyl)piperaZinyl]-2-[[[l-[[4-[2-(5- suitablebasic carrier, as for example an alkali metalcarchloropyrimidyl)]]]piperazinyl]]]ethane prepared by bonate orbicarbonate. We prefer to use sodium bicarreactingl-(fJ-chloroethyl)-4-phenylpiperazine with lbonate for this purpose. Thecondensation is preferably [2- (5- chloropyrimidyl)1piperazine; l -[1-(4- p-chlorocarried out at reflux temperature in the presence ofWaterphenyl)piperazinyl]-2 [[l-[4-(2-pyridyl)]piperazinyl]]- ethanol orother suitable organic solvents such as a ethane prepared by reactingl-(fi-chloroethyl)-4-p-chlorolower alkyl alcohol, chloroform or dioxane.phenylpiperazine with 1-(2-pyridy1)piperazine.

The resulting piperazine is then halogenated in the We claim: presenceof an inert solvent at a temperature varying 1. 1-[1- (4-phenyl)piperazinyl]-2-[[1-[4-(2-pyridyl)]- from about 0 C. to about 10C. Although the prepiperazinylflethane. ferred halogenating agent forthis reaction is thionyl chlo- 5 2, A method of preparing1-[l-(4-phenyl)piperazinyl]- ride, others may be used, as for examplephosphorus tri- 2-[[l-[4-(2-pyridy1)flpiperazinyl]] ethane whichcombromide, phosphorus pent-achloride or phosphorus oxyprises reactingl-(B-chloroethyl)-4-phenylpiperazine dichloride. The solvents we preferto use in this reaction hydrochloride with 1-(2-pyridyl)piperazine inthe presence are those of the non-hydroxylic type, as for example of aalkali metal bicarbonate. ether, chloroform, carbon tetrachloride,benzene, toluene 3, Compounds sele ted from the group consisting of andsimilar known carrier-s. those having the general formula The object ofthe condensation reaction is, of course, OHPCHI OHFOHQ to replace theavailable hydroxy group with a halogen. Once this is done, thesubstituted piperazine may be N (OH) N /N Ri further condensed withanother piperazine, the latter CHi-CH: OHFGHQ Preferably being employedin the form of its salt or free wherein n is a positive integer from 2to 10, R2 is a member base of the group consisting of pyridyl andpyrimidyl radicals The following examples illustrate our invention inand the therapeutically f l quaternary and i l more particular detail,but are not intended to be limitaaCid salts thereof tive upon the scopethereof. All parts are by weight un- 40 A method f pmparingunsymmetrical piperazines less otherwise indicated. having the general fla Example CHs-OE OHr-CH:

A solution consisting of 17.2 grams (0.06 mole) of (mink-Nl-(pB-chloroethyl 4 phenylpiperazine dihydrochloride, CHI-CHI QHPCH: 9.8grams (0.06 mole) of l-(2-pyridyl)piperazine, and h i n i a positiveinteger from 2 to 10 and R2 is a 20.2 grams (0.24 mole) of sodiumbicarbonate in 100 member f th group consisting of pyridyl and pyrimidylOf ethanol was refluxed aPpffiXimaiely 15 hours- At radicals whichcomprises the steps of reacting a member of the end of this time thissolution was concentrated to 0 the group consisting of N-pyridylpiperazine and N- a brown, oily residuewhich was made strongly alkalinei id l i a in with a 1-( mega-haloa1kyD-4- with concentrated potassiumhydroxide solution (10 m1.) ph l i in having the formula and extractedwith chloroform. The extract was treated OHPCHH with activated charcoal,dried over magnesium sulfate, 7

and concentrated under vacuum to a yellowish brown oil. womb-Hal Thisoily residue was treated with an 85% ethanol-water OKs-OH:

solution, and the granular material separated. The crude H 1 h 1 theyield of l-t-1-(4-phenyl)piperazinyll-2-[[1-[4-(2-pyrid- 22:23:3 '2 5: ig gg g gi and a 15 a Ogen m yl)-piperazinyl]]]ethane was recrystallizedfrom ethp 01- t l tio and melt d ov a constant ran e of 32- 1 8? so u ne 7 er a References Cited in the file of this patent Other compounds ofthe invention include 1-[1-(4- Davis et al.: J. Chem. Soc. (London),1949, 2831-4.

3. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEGENERAL FORMULA
 4. A METHOD OF PREPARING UNSYMMETRICAL PIPERAZINESHAVING THE GENERAL FORMULA